Project Summary/Abstract Major Depressive Disorder (MDD) is a highly prevalent and debilitating psychiatric syndrome marked by depressed mood and lack of interest. Stress is an important risk factor for MDD and often precipitates depressive episodes. Current antidepressant drugs require several weeks of treatment to achieve therapeutic efficacy and most patients do not achieve remission with the first antidepressant prescribed. These limitations of current antidepressant drugs highlight the need for a better understanding of the pathophysiology of MDD and identification of novel therapeutic targets. Clinical evidence suggests that MDD is associated with reduced concentrations of the inhibitory neurotransmitter ?-aminobutyric acid (GABA) in certain brain regions and reduced expression of GABAA receptors (GABAARs). Somatostatin (SST), a neuropeptide marker of a major subset of primarily dendrite-targeting GABAergic interneurons, is also reduced in certain brain regions of depressed patients. Reducing GABAergic synaptic transmission in mice by heterozygously deleting the ?2 subunit of GABAARs results in an anxious-depressive-like phenotype that includes HPA axis hyperactivity and is normalized by treatment with currently used antidepressants as well as subanesthetic doses of ketamine. Given these findings, we predicted that disinhibition of SST-positive (SST+) GABAergic interneurons through deletion of the ?2 subunit of GABAARs selectively in these neurons (SSTCre:?2f/f) would result in an antidepressant-like phenotype. Indeed, these mice show reduced depression-related behavior as well as reduced anxiety, along with enhanced GABAergic input to principal cells. Preliminary biochemical analyses of extracts from the hippocampus and medial prefrontal cortex (mPFC) of SSTCre:?2f/f mice further show reduced phosphorylation of eukaryotic elongation factor 2 (eEF2), consistent with corresponding changes in eEF2 phosphorylation upon treatment of rodents with three different classes of antidepressant drugs and suggestive of enhanced dendritic translation. Based on these findings we hypothesize that enhanced protein translation, particularly in dendrites of principal cells in the hippocampus and mPFC, may underlie the phenotype of SSTCre:?2f/f mice that mimics antidepressant drug treatment. The goal of this study is to determine whether SSTCre:?2f/f mice are resilient to unpredictable chronic mild stress (UCMS)-induced depressive behavior and to investigate the molecular mechanism underlying their anxiolytic and antidepressant-like phenotype. To this end, we will cross SSTCre:?2f/f mice and ?2f/f controls with a line of transgenic mice that express an epitope-tagged ribosomal subunit selectively in pyramidal cells of the hippocampus. This will allow us to isolate polysome-associated mRNAs from principal cells. RNAseq analysis of these mRNAs will then be used to identify transcripts that are differentially translated in SSTCre:?2f/f versus ?2f/f mice, either at baseline or following UCMS, with the hope of identifying novel candidate protein targets suitable for antidepressant drug therapies.